The objective of the proposed research is to investigate the potential of enzyme replacement therapy. The therapeutic effectiveness of enzyme replacement by the transplantation of enzyme-producing tissues and by the injection of purified, stabilized human enzymes will be determined. The initial focus for these studies will be enzyme therapy for Fabry (alpha-galactosidase A deficiency) and Gaucher Type 1 (Beta-glucocerebrosidase deficiency) diseases, lysosomal storage diseases without neural involvement. Enzyme therapy in these disorders by renal and isolated hepatocyte transplantation will be undertaken in appropriate patients and the long-term clinical and biochemical effectiveness will be evaluated. Direct enzyme replacement will be accomplished in a mammalian model system (Beta-glucuronidase deficient mice), cultured Fabry endothelial cells and selected patients. Sufficient quantities of normal human alpha-galactosidase A and Beta-glucocerebrosidase will be purified by combined affinity and conventional chromatographic techniques. These purified hydrolases will be chemically stabilized (cross-linked) using various bifunctional reagents. Administration strategies will include enzyme entrapment in liposomes and autologous erythrocytes; assessment of the in vivo fate and potential immunologic consequences of intravenously administered unentrapped and entrapped enzyme preparations will be accomplished in appropriate mammalian model systems. Endothelial cell culture will provide an in vitro system to evaluate the uptake of native vs various stabilized alpha-galactosidase A preparations. Clinical trials will be directed toward the application of these strategies to determine the biochemical and clinical effectiveness of enzyme therapy in patients with Fabry and Gaucher diseases. BIBLIOGRAPHIC REFERENCES: Desnick, R.J.: Batten's disease. In: The Dissection of a Degenerative Disease, Zeman, W. and Rider, J.A., eds., American Elsevier Publishing Co., New York, 1975, pp. 194-218. Desnick, R.J., Thorpe, S.R., and Fiddler, M.B.: Towards enzyme therapy for lysosomal storage diseases. Physiologic Rev., 56:57-99, 1976.